This project will describe the neuromuscular control of breathing during respiratory muscle fatigue in patients with chronic pulmonary and chronic neuromuscular disorders. Fatigue will be indicated by failure of the patient to maintain CO2 excretion equal to tissue CO2 production without a compensatory increase in arterial CO2 during the acute imposition of graded increases in mechanical (flow-resistive) loads upon the respiratory system. We will characterize the influence of chronic pulmonary and neuromuscular disease on thoracoabdominal mechanics and the detailed neuromuscular responses to mechanical and chemical stresses in these patients, by measurements of thoracoabdominal movements, intrathoracic and intra-abdominal pressure changes, electrical activity of respiratory muscles, and changes in arterial blood gas levels during the evolution of early stages of respiratory decompensation associated with mechanical loading. The responses observed in patients will be analyzed in terms of the relationships between thoracoabdominal mechanics and central and peripheral neural control of respiratory muscle activation. These responses will be interpreted in light of complementary physiological studies which will be carried out concurrently in the cat (anesthetized, decerebrate, and awake) and limited studies in normal humans measuring in addition the electrical activation of the levator costae and some of the intercostals from intramuscular wire electrodes. Our specific aims include the definition of the relationship between thoracoabdominal mechanics and peripheral and central neural control of respiratory muscles in the cat as a model of normal humans, in normal humans with particular reference to hitherto undescribed inspiratory muscles (the levator costae), and in patients with chronic pulmonary and neuromuscular disease. Our longterm objective is to simulate the natural course of events in patients with diminished reserves of respiratory muscle performance as they encounter mechanical and chemical stresses which may lead to respiratory disability and failure. We have put forth an hypothesis that such early acute failure is the result of central failure to provide sufficient and appropriate muscle stimulation. Comparisons between patients with defined neuromuscular and pulmonary disorders will help determine the extent of and probable sites of neuromuscular fatigue contributing to early respiratory failure in patients with chronic lung disease.